Loss of Resistin Improves Glucose Homeostasis in Leptin Deficiency

Abstract

Resistin levels are increased in obesity, and hyperresistinemia impairs glucose homeostasis in rodents. Here, we have determined the role of resistin in ob/ob mice that are obese and insulin resistant because of genetic deficiency of leptin. Loss of resistin increased obesity in ob/ob mice by further lowering the metabolic rate without affecting food intake. Nevertheless, resistin deficiency improved glucose tolerance and insulin sensitivity in these severely obese mice, largely by enhancing insulin-mediated glucose disposal in muscle and adipose tissue. In contrast, in C57BL/6J mice with diet-induced obesity but wild-type leptin alleles, resistin deficiency reduced hepatic glucose production and increased peripheral glucose uptake. Resistin deficiency enhanced Akt phosphorylation in muscle and liver and decreased suppressor of cytokine signaling-3 level in muscle, and these changes were reversed by resistin replacement. Together, these results provide strong support for an important role of resistin in insulin resistance and diabetes associated with genetic or diet-induced obesity. Diabetes 55:3083-3090, 2006 R esistin is a circulating protein derived from adipocytes in rodents and mononuclear cells in humans that has been implicated in obesityassociated diabetes (1). The secreted form of resistin is a trimer of disulfide-linked dimers of 9-kDa subunits (2,3). Hyperresistinemia created by acute resistin infusion or stable resistin gene transfer leads to insulin resistance and glucose intolerance because of increased hepatic glucose production (HGP) and, in some reports, inhibition of muscle glucose uptake, depending on the model being studied (4 -6). Conversely, resistin deficiency produced by deletion of the resistin gene or by antisense therapy improves insulin resistance and glucose metabolism (7,8). A dominant-negative form of resistin had a similar effect on glucose (9).Previous studies of the metabolic consequences of altered resistin levels have been performed in wild-type rodents (3-10). The role of resistin in the development of insulin resistance in ob/ob mice genetically lacking leptin is uncertain. As is the case in diet-induced obese (DIO) mice, adipose resistin gene expression is markedly decreased in ob/ob mice, yet serum resistin protein levels are increased (11,12). To clarify the role of resistin in insulin resistance and diabetes associated with leptin deficiency, we generated and analyzed ob/ob mice lacking resistin. Despite massive obesity caused by reduced energy expenditure, resistin deficiency in ob/ob mice resulted in improvements in glucose tolerance and insulin sensitivity, attributable largely to improved insulin sensitivity in muscle. In contrast, DIO resistin-null mice on similar C57BL/6J genetic background showed both a marked reduction in hepatic insulin resistance and increased peripheral glucose uptake. Thus, resistin contributes to insulin resistance and glucose intolerance in genetic and acquired obese states, although the tissue targets differ, potentially as a function of t...

Central Resistin Induces Hepatic Insulin Resistance via Neuropeptide Y

“…Experimental procedures were in accordance to institutional guidelines and regulations. Male C57BL/6J wild-type and npyϪ/Ϫ mice (Patel et al, 2006;Qi et al, 2006), were housed n ϭ 5 per cage in 12 h light/dark cycle (lights on 7:00 A.M.) and ambient temperature 22°C. Chow and water were provided ad libitum.…”

“…Increasing resistin levels through peripheral infusion or transgenic overexpression impairs insulin action (Pravenec et al, 2003;Patel et al, 2004;Rangwala et al, 2004;Satoh et al, 2004). Conversely, ablation of the retn gene or reduction of resistin via antisense oligonucleotide treatment enhances insulin sensitivity, leading to a decrease in hepatic glucose production and increase in glucose uptake by muscle and adipose tissue Muse et al, 2004;Qi et al, 2006). Furthermore, studies suggest that the increase in resistin after high-fat feeding is the primary cause of hepatic insulin resistance (Muse et al, 2004;Qi et al, 2006).…”

“…Conversely, ablation of the retn gene or reduction of resistin via antisense oligonucleotide treatment enhances insulin sensitivity, leading to a decrease in hepatic glucose production and increase in glucose uptake by muscle and adipose tissue Muse et al, 2004;Qi et al, 2006). Furthermore, studies suggest that the increase in resistin after high-fat feeding is the primary cause of hepatic insulin resistance (Muse et al, 2004;Qi et al, 2006). Resistin regulates molecules involved in the signal transduction of insulin, leptin and various adipokines, although the receptor has not been identified Muse et al, 2004;Satoh et al, 2004;Steppan et al, 2005).…”

Obesity, inflammation, and insulin resistance

“…Ob-ob resistin deficient mice were more obese although showing increased insulin sensitivity and improved glucose tolerance (Qi et al, 2006).…”

Inflammation in Obesity is a Common Link Between Defects in Fatty Acid Metabolism and Insulin Resistance

“…Another potentially important player involved with the continued suppression of AMPK signaling may be the cytokine resistin which is elevated in obesity 87 and has been shown to suppress AMPK signaling in obese skeletal muscle. 88 Future studies are required to examine the mechanisms by which resistin impairs AMPK signaling in obesity. Interestingly, while 48 hours of TNFα neutralization restored AMPK signaling to that of lean controls it resulted in no noticeable improvement in skeletal muscle insulin sensitivity compared with obese ob/ob mice.…”